title: Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism.
abstract: Mutations in the daf-2 gene of the conserved Insulin/Insulin-like Growth Factor (IGF-1) pathway double the lifespan of the nematode Caenorhabditis elegans. This phenotype is completely suppressed by deletion of Forkhead transcription factor daf-16. To uncover regulatory mechanisms coordinating this extension of life, we employed a quantitative proteomics strategy with daf-2 mutants in comparison with N2 and daf-16; daf-2 double mutants. This revealed a remarkable longevity-specific decrease in proteins involved in mRNA processing and transport, the translational machinery, and protein metabolism. Correspondingly, the daf-2 mutants display lower amounts of mRNA and 20S proteasome activity, despite maintaining total protein levels equal to that observed in wild types. Polyribosome profiling in the daf-2 and daf-16;daf-2 double mutants confirmed a daf-16-dependent reduction in overall translation, a phenotype reminiscent of Dietary Restriction-mediated longevity, which was independent of germline activity. RNA interference (RNAi)-mediated knockdown of proteins identified by our approach resulted in modified C. elegans lifespan confirming the importance of these processes in Insulin/IGF-1-mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF-1-mediated extension of life.
authors.affiliation: University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Molecular Cancer Research, Section Metabolic Diseases, Utrecht, The Netherlands.
authors.forename: Gerdine J
authors.initials: GJ
authors.lastname: Stout
authors.forename: Edwin C A
authors.initials: EC
authors.lastname: Stigter
authors.forename: Paul B
authors.initials: PB
authors.lastname: Essers
authors.forename: Klaas W
authors.initials: KW
authors.lastname: Mulder
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kolkman
authors.forename: Dorien S
authors.initials: DS
authors.lastname: Snijders
authors.forename: Niels J F
authors.initials: NJ
authors.lastname: van den Broek
authors.forename: Marco C
authors.initials: MC
authors.lastname: Betist
authors.forename: Hendrik C
authors.initials: HC
authors.lastname: Korswagen
authors.forename: Alyson W
authors.initials: AW
authors.lastname: Macinnes
authors.forename: Arjan B
authors.initials: AB
authors.lastname: Brenkman
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005838:Genotype; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D046988:Proteasome Endopeptidase Complex